Analysis of the impact of adherence to guidelines and expert advice in patients with myelodysplastic syndromes.

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract.

Increased cardiovascular comorbidities in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia presenting with systemic inflammatory and autoimmune manifestations.

Myelodysplastic syndromes (MDS) and associated diseases, like chronic myelomonocytic leukemias (CMML), are heterogeneous, clonal disorders affecting the hematopoietic stem cells. They are characterized by dysplasia and a propensity to evolve toward acute myeloid leukemia. Systemic inflammatory and autoimmune manifestations (SIAMs) occur with a prevalence of 10% to 20% in myeloid malignancies, but the underlying pathogenetic mechanisms remain obscure. In this study, we aimed to characterize patient- and disease-based differences in MDS and CMML patients with and without SIAMs and explore the impact of SIAMs on progression and survival. We performed a retrospective, single-centre, and case-control study in a cohort of 93 patients diagnosed with MDS and CMML between 01/2008 and 12/2015. Thirty patients (32%) were identified with SIAMs: musculoskeletal and connective tissue (26.8%), vascular (19.5%), systemic autoinflammation (17%), skin (12.2%), gastrointestinal (9.8%), and others (14.6%). SIAMs were treated with glucocorticoids (60%), methotrexate (16.7%), biologicals (13.3%), and cyclosporine (3.3%). No significant differences between the SIAM and non-SIAM patients were observed in age, gender, or previous exposure to cancer treatment. Cardiovascular comorbidities were significantly more frequent in patients with SIAMs (63.1% vs 90%; OR 5.5; P < .01), but no differences were observed for other comorbidities or IPSS and IPSS-R risk scores. CMML and refractory anemia with excess blasts 1/2 subtypes were by tendency more frequent in patients with and refractory cytopenia with multilineage dysplasia (RCMD) in those without SIAMs. Finally, time to progression, leukemia free survival and overall survival were similar for both groups. Despite patient heterogeneity and small cohort size, we were able to identify a significant association of SIAMs with cardiovascular comorbidities but without influence on progression or survival.

HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias.

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.

PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream enhancer element.

The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-kappaB (NF-kappaB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-kappaB site in 4 of 120 AML patients. These variant NF-kappaB sequences failed to mediate activation of PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML.

Boletus edulis: a digestion-resistant allergen may be relevant for food allergy.

BACKGROUND: Fungal components can cause allergic symptoms either through inhalation, ingestion or contact. Whereas respiratory allergy is thought to be induced by spores, allergic reactions following ingestion are attributed to other parts of the mushroom. Reports of food-related allergic reactions due to the edible mushroom Boletus edulis have occasionally been reported. OBJECTIVE: The aim of the study was to investigate whether separate allergens may be detected in alimentary allergy to Boletus edulis. METHODS: Sera of two subjects, one with recurrent anaphylaxis and the other with a predominantly oral allergy syndrome following ingestion of Boletus edulis, have been analysed by a time-course digestion assay using simulated gastric fluid and by SDS-PAGE immunoblotting. Sera of four Boletus edulis skin prick test-negative subjects and all without clinical symptoms to ingested Boletus edulis served as controls. RESULTS: In lyophilized Boletus edulis extract, at least four water-soluble proteins were detected, the most reactive at 55 kDa and at 80 kDa. Following the time-course digestion assay, IgE binding was found to a 75-kDa protein, but only if the sera of the subject with recurrent anaphylaxis was used. CONCLUSION: The data indicate that Boletus edulis can cause an IgE-mediated food allergy due to a digestion-stabile protein at 75 kDa. No IgE immune response to this protein was detected in the serum of a subject with respiratory allergy and oral allergy syndrome to Boletus edulis nor in control sera.